ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1233T>G (p.Asp411Glu)

gnomAD frequency: 0.00012  dbSNP: rs80357024
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV000083166 SCV004101451 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-10-08 reviewed by expert panel curation The c.1233T>G variant in BRCA1 is a missense variant predicted to cause substitution of Aspartic acid by Glutamic acid at amino acid 411 (p.Asp411Glu). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.0002413 in the African/African American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.0001) for BS1, and below the BA1 threshold (>0.001) (BS1 met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.07, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1, BP1_Strong, BS3).
Invitae RCV001080838 SCV000075400 likely benign Hereditary breast ovarian cancer syndrome 2024-01-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130781 SCV000185674 likely benign Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV000428573 SCV000517031 likely benign not specified 2017-11-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034726 SCV000600244 likely benign not provided 2019-12-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000428573 SCV000698836 likely benign not specified 2023-04-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1233T>G (p.Asp411Glu) results in a conservative amino acid change located in the serine-rich domain (IPR025994) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 349536 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. Though this frequency is not higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00049 vs 0.001), the variant might still represent a benign polymorphism. In addition, the variant was also reported in 1/7325 European American women (frequency: 0.00014) and 2/2559 African American women (frequency: 0.0008), who were older than age 70 years and have never had cancer (in the FLOSSIES database). Overall, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1233T>G has been reported in the literature as a VUS in settings of multigene panel testing/custom genotyping arrays in cohorts of individuals with breast cancer (example, Maxwell_2014, Judkins_2005, Abkevich_2004, Shimelis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000130781 SCV000903235 benign Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000130781 SCV002538005 likely benign Hereditary cancer-predisposing syndrome 2020-12-07 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV000083166 SCV004818359 benign Breast-ovarian cancer, familial, susceptibility to, 1 2024-02-05 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034726 SCV000043182 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000083166 SCV000115240 benign Breast-ovarian cancer, familial, susceptibility to, 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083166 SCV000144035 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356304 SCV001551433 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp411Glu variant was identified in 1 of 556 proband chromosomes (frequency: 0.001798) from individuals or families with early onset breast cancer (Maxwell_2014), and was found in 1 of 1144 chromosomes in an exome sequencing study of a control population of individuals with atherosclerosis (Johnston_2012). The variant was also identified in dbSNP (ID: rs80357024) as “With other allele”, ClinVar (as benign by SCRP, likely benign by Invitae, Ambry Genetics, and GeneDx, and uncertain significance by Quest Diagnostics, BIC and Biesecker Lab), Clinvitae (5x), LOVD 3.0 (3x), UMD-LSDB (4x), and BIC Database (4x) databases. The variant was not identified in COGR, Cosmic, MutDB, ARUP Laboratories, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 11 of 276576 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 10 of 24008 chromosomes (freq: 0.000417), Latino in 1 of 34402 chromosomes (freq: 0.000029), and not in the Other, European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. There are conflicting interpretations in the literature for this variant. Studies based on amino acid conservation classify the variant as neutral (Abkevich_2004, Burk-Herrick_2005), while a study of splicing effects (Mucaki_2010) and a study of early onset breast cancer patients (Maxwell_2014) both classified the variant as unknown significance. The p.Asp411 residue is not conserved in mammals and the variant amino acid Glutamine (Glu) is present in Red junglefowl, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site. However, HumanSpliceFinder, MaxEntScan, and GeneSplicer predict an altered 5' splice site in this region and Human Splicing Finder predicts an altered 3’ splice site; therefore we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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